Soluble urokinase plasminogen activator receptor and interleukin‐6 improves prediction of all‐cause mortality and major adverse cardiovascular events in Type 1 diabetes

Abstract Background Type 1 diabetes (T1D) increases premature mortality risk, with cardiovascular disease being the leading cause. Chronic inflammation may play a role. Associations between inflammatory biomarkers and mortality are not well‐known in T1D. Methods We evaluated a prospective clinical cohort with T1D without known cardiovascular disease. The inflammatory biomarkers soluble‐urokinase‐plasminogen‐activator‐receptor (suPAR) and interleukin‐6 (IL‐6) were measured. Patients were stratified by elevated/low suPAR or IL‐6, or simultaneously elevated suPAR and IL‐6. Primary and secondary endpoints were all‐cause mortality and major adverse cardiovascular events (MACE), respectively. Cox models were adjusted for 10 Steno T1 Risk Engine variables and inflammatory biomarkers. Net reclassification improvement (NRI) and C‐statistics were calculated. Results Among 962 participants (52% male, median age 50, median follow‐up 13.1 years), mortality was higher in patients with elevated inflammation: 31% for elevated versus 9% for low suPAR; 30% for elevated versus 11% for low IL‐6; and 50% for simultaneously elevated suPAR and IL‐6 versus 5% for low suPAR and IL‐6. In fully adjusted models, elevated inflammation was associated with mortality (hazard ratios [95% confidence intervals]: suPAR 2.0 [1.4–3.0, p < 0.001], IL‐6 1.8 [1.3–2.6; p = 0.001], and combined 4.0 [2.3–7.2, p < 0.001]) and MACE (suPAR 1.9 [1.4–2.6, p < 0.001], IL‐6 1.4 [1.0–1.8, p = 0.034], and combined 2.6 [1.7–4.1, p < 0.001]). Adding suPAR, IL‐6, and their combination to the Steno T1 Risk Engine improved NRI for mortality by 61%, 53%, and 84%, respectively, whereas C‐statistics improved from 0.808 to 0.829, 0.826, and 0.881, respectively. Conclusions suPAR, IL‐6, and especially their combination independently predicts all‐cause mortality and MACE in T1D without known cardiovascular disease.